Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**
作者:Muthusamy Jayaraman、Steven M. Ansell、Barbara L. Mui、Ying K. Tam、Jianxin Chen、Xinyao Du、David Butler、Laxman Eltepu、Shigeo Matsuda、Jayaprakash K. Narayanannair、Kallanthottathil G. Rajeev、Ismail M. Hafez、Akin Akinc、Martin A. Maier、Mark A. Tracy、Pieter R. Cullis、Thomas D. Madden、Muthiah Manoharan、Michael J. Hope
DOI:10.1002/anie.201203263
日期:2012.8.20
Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipidnanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2–6.5 (see graph). The most potent cationic lipid from this study
特殊(脂质)递送:通过对脂质进行大量头基修饰,研究了可电离脂质 p K a在脂质纳米粒子体内递送 siRNA 中的作用。脂质P的的紧密相关ķ一个 值和鼠标FVII基因(FVII ED的沉默50)被发现,具有最佳p ķ一个范围的6.2-6.5(见图)。本研究中最有效的阳离子脂质的 ED 50水平在小鼠中约为 0.005 mg kg -1,在非人类灵长类动物中低于 0.03 mg kg -1。
METHODS AND COMPOSITIONS FOR DELIVERY OF NUCLEIC ACIDS
The invention provides a nucleic acid comprising a Cpf1 crRNA, a processing sequence 5' of the Cpf1 crRNA, and an extension sequence 5' of the processing sequence. The invention also provides a composition comprising the nucleic acid, a carrier, and optionally Cpf1. Additionally, the invention provides method of genetically modifying a eukaryotic target cell, comprising contacting the eukaryotic target cell with the nucleic acid or the composition to genetically modify a target nucleic acid in the cell.